It is now generally recognized that differences in sensitivity to the effects of ethanol, and the development of tolerance to and dependence on ethanol is under genetic as well as environmental regulation. However, the mechanism by which ethanol produces its effects and the way genotypic factors modulates the response of animals to ethanol is still poorly understood. One strategy for investigating these questions involves the selective breeding of mouse lines which differ in specific behavioral responses to ethanol and the study of correlated behavioral and neurochemical responses to selection. Finding a correlated neurochemical response would imply that the correlated response must be influenced by some genes in common with the selected response and suggest that the altered neurochemical pathway may be involved in ethanol's mechanism of action. We are currently breeding lines of mice which differ in two responses to an acute dose of ethanol: hypothermia (TEMP) lines which are susceptible (COLD) and resistant (HOT) to the effect of ethanol on body temperature, and activity (OFA) lines which are prone (FAST) and resistant (SLOW) to increased activity caused by ethanol. The parallel study of correlated neurochemical responses during selection for a behavioral response has never been reported. The goal of this proposal is the identification and systematic study of correlated responses in specific and relevant neurotransmitter systems during the selection process for the TEMP and OFA lines. One main hypothesis of this proposal, based on physiological and pharmacological data, is that the catecholaminergic and serotonergic systems mediate ethanol's effect in the TEMP lines, and that the catecholaminergic pathways mediate the differences in the OFA lines. Initially, I plan to measure the levels of DA, NE, 5-HT and their metabolites, and characterize the binding properties of their receptors in mice that have received an acute dose of ethanol. These experiments should provide a rapid and sensitive measure of changes occurring in each pathway. Based on the outcome of these studies I will design experiments focussing in more detail in the specific systems affected, particularly the second messengers and neurotransmitter release. The successful completion of this proposal will increase our understanding of how ethanol causes its behavioral effects and how genotype regulates sensitivity to ethanol.
